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Mining the ubiquitin system for catalytic activities through advanced ubiquitin probes

Objective

I propose a chemoproteomic platform for the discovery of unchartered eraser activities regulating post-translational modifications within the ubiquitin system. This approach will be enabled by a suite of advanced ubiquitin probes. These reagents recapitulate the complexity of cellular polyubiquitin modifications and are equipped with novel electrophilic handles to report on polyubiquitin chain length- and linkage-dependent activities of deubiquitinating enzymes. These enzymes reverse ubiquitin modifications and critically determine the outcome of ubiquitin-mediated signalling, yet how they decode ubiquitin chains has remained poorly understood. Moreover, activity-based probes with novel designs will enable chemoproteomic experiments to identify enzymes with novel catalytic mechanisms and with relevance in cellular stress response processes. These insights will subsequently reveal molecular mechanisms of chain-length decoding and substrate recognition by facilitating the structural analysis of DUB-probe complexes. Taken together, the proposed work breaks new ground through a rational workflow for comprehensively mining the proteome for unprecedented DUB/Ubl eraser activities. Expected results will have broad implications also for ubiquitin assembly enzymes, pathogen-derived virulence factors and other protein classes. UbiPRO will thus illuminate a fundamentally important and evolutionarily conserved system of molecular information encoding employed by all forms of life.

Fields of science (EuroSciVoc)

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Programme(s)

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Topic(s)

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Funding Scheme

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HORIZON-ERC - HORIZON ERC Grants

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Call for proposal

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(opens in new window) ERC-2025-COG

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Host institution

UNIVERSITAET DUISBURG-ESSEN
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 1 999 721,00
Address
UNIVERSITATSSTRASSE 2
45141 ESSEN
Germany

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Region
Nordrhein-Westfalen Düsseldorf Essen, Kreisfreie Stadt
Activity type
Higher or Secondary Education Establishments
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Total cost

The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.

€ 1 999 721,00

Beneficiaries (2)

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